title: Secreted bacterial effectors that inhibit host protein synthesis are critical for induction of the innate immune response to virulent Legionella pneumophila.
abstract: The intracellular bacterial pathogen Legionella pneumophila causes an inflammatory pneumonia called Legionnaires' Disease. For virulence, L. pneumophila requires a Dot/Icm type IV secretion system that translocates bacterial effectors to the host cytosol. L. pneumophila lacking the Dot/Icm system is recognized by Toll-like receptors (TLRs), leading to a canonical NF-κB-dependent transcriptional response. In addition, L. pneumophila expressing a functional Dot/Icm system potently induces unique transcriptional targets, including proinflammatory genes such as Il23a and Csf2. Here we demonstrate that this Dot/Icm-dependent response, which we term the effector-triggered response (ETR), requires five translocated bacterial effectors that inhibit host protein synthesis. Upon infection of macrophages with virulent L. pneumophila, these five effectors caused a global decrease in host translation, thereby preventing synthesis of IκB, an inhibitor of the NF-κB transcription factor. Thus, macrophages infected with wildtype L. pneumophila exhibited prolonged activation of NF-κB, which was associated with transcription of ETR target genes such as Il23a and Csf2. L. pneumophila mutants lacking the five effectors still activated TLRs and NF-κB, but because the mutants permitted normal IκB synthesis, NF-κB activation was more transient and was not sufficient to fully induce the ETR. L. pneumophila mutants expressing enzymatically inactive effectors were also unable to fully induce the ETR, whereas multiple compounds or bacterial toxins that inhibit host protein synthesis via distinct mechanisms recapitulated the ETR when administered with TLR ligands. Previous studies have demonstrated that the host response to bacterial infection is induced primarily by specific microbial molecules that activate TLRs or cytosolic pattern recognition receptors. Our results add to this model by providing a striking illustration of how the host immune response to a virulent pathogen can also be shaped by pathogen-encoded activities, such as inhibition of host protein synthesis.
authors.affiliation: Department of Molecular and Cell Biology, Division of Immunology and Pathogenesis, University of California, Berkeley, Berkeley, California, USA.
authors.forename: Mary F
authors.initials: MF
authors.lastname: Fontana
authors.forename: Simran
authors.initials: S
authors.lastname: Banga
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Barry
authors.forename: Xihui
authors.initials: X
authors.lastname: Shen
authors.forename: Yunhao
authors.initials: Y
authors.lastname: Tan
authors.forename: Zhao-Qing
authors.initials: ZQ
authors.lastname: Luo
authors.forename: Russell E
authors.initials: RE
authors.lastname: Vance
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D054884:Host-Pathogen Interactions / Q000502:physiology; D020672:I-kappa B Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007113:Immunity, Innate / Q000502:physiology; D016952:Legionella pneumophila / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity* / Q000502:physiology; D007877:Legionnaires' Disease / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000378:metabolism; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014176:Protein Biosynthesis / Q000276:immunology*; D021381:Protein Transport; D015398:Signal Transduction / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins; C440002:DotA protein, Legionella pneumophila; D020672:I-kappa B Proteins; C503175:IcmS protein, Legionella pneumophila; D008565:Membrane Proteins; D018832:Molecular Chaperones; D016328:NF-kappa B; D051193:Toll-Like Receptors; D014157:Transcription Factors; D037521:Virulence Factors